Hepatitis B virus (HBV) infection is a common infectious disease. Here we perform a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci involved in persistent HBV infection. GWAS scan is performed in 1,251 persistently HBV infected subjects (PIs, cases) and 1,057 spontaneously recovered subjects (SRs, controls), followed by replications in four independent populations totally consisting of 3,905 PIs and 3,356 SRs. We identify a novel locus at 8p21.3 (index rs7000921, odds ratio=0.78, P=3.2 × 10⁻¹²). Furthermore, we identify significant expression quantitative trait locus associations for INTS10 gene at 8p21.3. We demonstrate that INST10 suppresses HBV replication via IRF3 in liver cells. In clinical plasma samples, we confirm that INST10 levels are significantly decreased in PIs compared with SRs, and negatively correlated with the HBV load. These findings highlight a novel antiviral gene INTS10 at 8p21.3 in the clearance of HBV infection.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In this study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC. Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls. Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, OR = 1.28, P = 9.46 × 10−10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10272859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients. Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus. Clin Cancer Res; 24(4); 906–15. ©2017 AACR.

Background: Chemokines play important roles in inflammation and antiviral action. We examined whether polymorphisms ofRANTES, IP-10andMigaffect the susceptibility to and outcome of severe acute respiratory syndrome (SARS).Methods: We tested the polymorphisms ofRANTES, IP-10andMigfor their associations with SARS in 495 Hong Kong Chinese SARS patients and 578 controls. Then we tried to confirm the results in 356 Beijing Chinese SARS patients and 367 controls.Results: RANTES-28 G allele was associated with SARS susceptibility in Hong Kong Chinese (P< 0.0001, OR = 2.80, 95%CI:2.11–3.71). Individuals withRANTES-28 CG and GG genotypes had a 3.28-fold (95%CI:2.32–4.64) and 3.06-fold (95%CI:1.47–6.39) increased risk of developing SARS respectively (P< 0.0001). This -28 G allele conferred risk of death in a gene-dosage dependent manner (P= 0.014) with CG and GG individuals having a 2.12-fold (95% CI: 1.11–4.06) and 4.01-fold (95% CI: 1.30–12.4) increased risk. For the replication ofRANTESdata in Beijing Chinese, the -28 G allele was not associated with susceptibility to SARS. However, -28 CG (OR = 4.27, 95%CI:1.64–11.1) and GG (OR = 3.34, 95%CI:0.37–30.7) were associated with admission to intensive care units or death due to SARS (P= 0.011).Conclusion: RANTES-28 G allele plays a role in the pathogenesis of SARS.

How the complexity or irregularity of heart rate variability (HRV) changes across different sleep stages and the importance of these features in sleep staging are not fully understood. This study aimed to investigate the complexity or irregularity of the RR interval time series in different sleep stages and explore their values in sleep staging. We performed approximate entropy (ApEn), sample entropy (SampEn), fuzzy entropy (FuzzyEn), distribution entropy (DistEn), conditional entropy (CE), and permutation entropy (PermEn) analyses on RR interval time series extracted from epochs that were constructed based on two methods: (1) 270-s epoch length and (2) 300-s epoch length. To test whether adding the entropy measures can improve the accuracy of sleep staging using linear HRV indices, XGBoost was used to examine the abilities to differentiate among: (i) 5 classes [Wake (W), non-rapid-eye-movement (NREM), which can be divide into 3 sub-stages: stage N1, stage N2, and stage N3, and rapid-eye-movement (REM)]; (ii) 4 classes [W, light sleep (combined N1 and N2), deep sleep (N3), and REM]; and (iii) 3 classes: (W, NREM, and REM). SampEn, FuzzyEn, and CE significantly increased from W to N3 and decreased in REM. DistEn increased from W to N1, decreased in N2, and further decreased in N3; it increased in REM. The average accuracy of the three tasks using linear and entropy features were 42.1%, 59.1%, and 60.8%, respectively, based on 270-s epoch length; all were significantly lower than the performance based on 300-s epoch length (i.e., 54.3%, 63.1%, and 67.5%, respectively). Adding entropy measures to the XGBoost model of linear parameters did not significantly improve the classification performance. However, entropy measures, especially PermEn, DistEn, and FuzzyEn, demonstrated greater importance than most of the linear parameters in the XGBoost model.300-s270-s.

Background: Increases in human telomerase reverse transcriptase (TERT) expression and telomerase activity are frequently seen in nasopharyngeal carcinoma (NPC). Recently, a variable tandem-repeats polymorphism, MNS16A, located in the downstream region of the TERT gene, was identified and reported to have an effect on TERT expression and telomerase activity. We examined whether the functional MNS16A was related to the risk of occurrence or progression of NPC in the Chinese population. Methods: We genotyped the MNS16A polymorphism in a case-control study of 855 patients with NPC and 1036 cancer-free controls using PCR, and determined genotype by classifying the DNA band of 243 or 272 base pairs (bp) as the short (S) allele and 302 or 333 bp as the long (L) allele. The genetic associations with the risk of NPC were analyzed by logistic regression. Results: The MNS16A genotype was not associated with the progression of NPC. However, individuals carrying the S alleles (SL + SS genotype) had a significantly reduced risk of NPC occurrence compared with those carrying the LL genotype (odds ratio (OR) = 0. 71, 95% confidence interval (CI) = 0. 52 to 0. 96, P = 0. 025). Using a immunohistochemical assay on the NPC tissues, the SL genotype carriers were found to have lower TERT expression than the LL genotype carriers (P = 0. 035). Conclusions: Our study indicates that the TERT MNS16A polymorphism may contribute to the risk of NPC onset in Chinese population.

Argonaute 2 (AGO2), a central component of RNA-induced silencing complex, plays critical roles in cancer. We examined whether the single nucleotide polymorphisms (SNPs) of AGO2 were related to the risk of nasopharyngeal carcinoma (NPC). Twenty-five tag SNPs within AGO2 were genotyped in Guangxi population consisting of 855 NPC patients and 1036 controls. The SNPs significantly associated with NPC were further replicated in Guangdong population consisting of 996 NPC patients and 972 controls. Functional experiments were conducted to examine the biologic roles of AGO2 in NPC. A significantly increased risk of advanced lymph node metastasis of NPC was identified for the AGO2 rs3928672 GA + AA genotype compared with GG genotype in both the Guangxi and Guangdong populations (combined odd ratio = 2.08, 95 % confidence interval = 1.44-3.01, P = 8.60 × 10−5). Moreover, the AGO2 protein expression levels of rs3928672 GA + AA genotype carriers were higher than the GG genotype carriers in the NPC tissues (P = 0.041), and AGO2 was significantly over-expressed in NPC tissues compared with non-cancerous nasopharyngeal tissues (P = 0.011). In addition, AGO2 knockdown reduced cell proliferation, induced apoptosis, and inhibited migration of NPC cells. Furthermore, gene expression microarray showed that genes altered following AGO2 knockdown were clustered in tumorigenesis and metastasis relevant pathways. Our findings suggest that the genetic polymorphism in AGO2 may be a risk factor for the advanced lymph node metastasis of NPC in Chinese populations, and AGO2 acts as an oncogene in the development of NPC.